Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Methanogens in humans : potentially beneficial or harmful for health

Methanogens are anaerobic prokaryotes from the domain archaea that utilize hydrogen to reduce carbon dioxide, acetate, and a variety of methyl compounds into methane. Earlier believed to inhabit only the extreme environments, these organisms are now reported to be found in various environments including mesophilic habitats and the human body. The biological significance of methanogens for humans has been re-evaluated in the last few decades. Their contribution towards pathogenicity has received much less attention than their bacterial counterparts. In humans, methanogens have been studied in the gastrointestinal tract, mouth, and vagina, and considerable focus has shifted towards elucidating their possible role in the progression of disease conditions in humans. Methanoarchaea are also part of the human skin microbiome and proposed to play a role in ammonia turnover. Compared to hundreds of different bacterial species, the human body harbors only a handful of methanogen species represented by Methanobrevibacter smithii, Methanobrevibacter oralis, Methanosphaera stadtmanae, Methanomassiliicoccus luminyensis, Candidatus Methanomassiliicoccus intestinalis, and Candidatus Methanomethylophilus alvus. Their presence in the human gut suggests an indirect correlation with severe diseases of the colon. In this review, we examine the current knowledge about the methanoarchaea in the human body and possible beneficial or less favorable interactions

Honeys with anti-inflammatory capacity can alter the elderly gut microbiota in an ex vivo gut model

The anti-inflammatory effect of different sourced honeys and the impact on elderly gut microbiota were studied in terms of chemical compositions, anti-inflammatory effect and gut microbiota modulating capacities. All four honeys suppressed the production of pro-inflammatory markers NO, IL-1β and IL-6 induced by lipopolysaccharide and promoted the expression of anti-inflammatory cytokines IL-10 in RAW 264.7 cells. Moreover, in the ex vivo batch gut model using elderly fecal microbiota (referred to as microcosm), it was showed that the addition of honeys increased the abundance of beneficial lactobacilli, decreased the abundance of potentially harmful Gram negative enteric bacteria, and exerted a beneficial effect on the production of short chain fatty acids. The concentration of gallic acid in honeys was positively correlated with the expression level of IL-10 and the abundance of lactobacilli. These findings indicate honeys with anti-inflammatory capacity have great potential for regulating the elderly gut microbiota which would lead to health benefits.Nanyang Technological UniversityWe sincerely thank the support from the funding of China Scholarship Council (grant no. 201906240301)

In vitro profiling of potential fish probiotics, Enterococcus hirae spp., isolated from jade perch Scortum barcoo and safety properties assessed using whole genome sequencing

Exploiting the use of probiotics in aquaculture is one key strategy to promote fish growth while mitigating fish-associated diseases. Among the different types of probiotics, host-derived probiotics exhibit promising efficacy compared to commercial or terrestrial-derived ones as they are adapted to the host environment. This study aimed to identify and characterize potential probiotics from jade perch (Scortum barcoo), one of the newly farmed fish species in Singapore, to enhance its disease resistance. Gut isolates from jade perch were screened for their ability to inhibit the growth of pathogenic Aeromonas sobria, Streptococcus iniae, and Streptococcus agalactiae. Several isolates that demonstrated antagonistic effects against A. sobria and S. iniae were later identified to be Enterococcus hirae. The pathogen inhibition efficacy of this isolate was also examined in both jade perch and tilapia gut suspensions, mimicking more complex host microbial environments. Significant clear zones were found when co-incubated with jade perch gut suspensions, whereas only minimal inhibition zones were produced in tilapia gut suspensions, suggesting the advantage of using host-derived probiotics. The safety of the final probiotic candidate was evaluated using whole-genome sequencing. This strain did not harbor any known toxins and mobile genetic elements. Conjugation experiments confirmed that its inherent antibiotic resistance gene aac (6')-Iid was not transferable. Two classes of bacteriocins were found in the probiotic genome, which partially explained its antimicrobial activities against both Gram-positive and Gram-negative pathogens. The use of E. hirae as a probiotic for Jade Perch and other freshwater fish is promising as it is acclimatized to aquatic environments, safe and effective.Nanyang Technological Universit

In Vitro Utilization of Amylopectin and High-Amylose Maize (Amylomaize) Starch Granules by Human Colonic Bacteria

It has been well established that a certain amount of ingested starch can escape digestion in the human small intestine and consequently enters the large intestine, where it may serve as a carbon source for bacterial fermentation. Thirty-eight types of human colonic bacteria were screened for their capacity to utilize soluble starch, gelatinized amylopectin maize starch, and high-amylose maize starch granules by measuring the clear zones on starch agar plates. The six cultures which produced clear zones on amylopectin maize starch- containing plates were selected for further studies for utilization of amylopectin maize starch and high-amylose maize starch granules A (amylose; Sigma) and B (Culture Pro 958N). Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) was used to detect bacterial starch-degrading enzymes. It was demonstrated that Bifidobacterium spp., Bacteroides spp., Fusobacterium spp., and strains of Eubacterium, Clostridium, Streptococcus, and Propionibacterium could hydrolyze the gelatinized amylopectin maize starch, while only Bifidobacterium spp. and Clostridium butyricum could efficiently utilize high-amylose maize starch granules. In fact, C. butyricum and Bifidobacterium spp. had higher specific growth rates in the autoclaved medium containing high-amylose maize starch granules and hydrolyzed 80 and 40% of the amylose, respectively. Starch-degrading enzymes were cell bound on Bifidobacterium and Bacteroides cells and were extracellular for C. butyricum. Active staining for starch-degrading enzymes on SDS-PAGE gels showed that the Bifidobacterium cells produced several starch-degrading enzymes with high relative molecular (M(r)) weights (>160,000), medium-sized relative molecular weights (>66,000), and low relative molecular weights (<66,000). It was concluded that Bifidobacterium spp. and C. butyricum degraded and utilized granules of amylomaize starch

Identification of arenin, a novel Kunitz-like polypeptide from the skin secretions of Dryophytes arenicolor

Amphibian skin secretions are enriched with complex cocktails of bioactive molecules such as proteins, peptides, biogenic amines, alkaloids guanidine derivatives, steroids and other minor components spanning a wide spectrum of pharmacological actions exploited for centuries in folk medicine. This study presents evidence on the protein profile of the skin secretions of the canyon tree frog, Dryophytes arenicolor. At the same time, it presents the reverse-phase liquid chromatography isolation, mass spectrometry characterization and identification at mRNA level of a novel 58 amino acids Kunitz-like polypeptide from the skin secretions of Dryophytes arenicolor, arenin. Cell viability assays performed on HDFa, CaCo2 and MCF7 cells cultured with different concentrations of arenin showed a discrete effect at low concentrations (2, 4, 8 and 16 µg/mL) suggesting a multi-target interaction in a hormetic-like dose-response. Further work is required to investigate the mechanisms underlying the variable effect on cell viability produced by different concentrations of arenin.Published versio

Ex vivo evaluation of the polysaccharide-encapsulated, host-derived microbial compositions on the gut microbiota of jade perch (scortum barcoo)

Probiotics have been recognized as a bio-control measure in aquaculture against bacterial infections, especially with the surge of antibiotic-resistant pathogens. To fully exert the benefits of host-derived probiotics, which are well adapted to prevailing environmental conditions, microencapsulation is often needed to prevent them from gastric acidity, storage, and feed preparation processes before reaching the targeted sites and releasing in a desired manner. Common encapsulants include polysaccharides and proteins, immobilizing probiotics in a 3D matrix to maintain their viability and effectiveness. It is worth noticing that some of these encapsulants are seaweed-derived, which can be viable candidates as prebiotics when served as dietary supplements. Therefore, this work evaluated how four common polysaccharide encapsulants, alginate, carrageenan, xanthan, and gum arabic, can be utilized to modulate the host gut microbiota in an ex vivo model. Alginate and kappa-carrageenan were shortlisted for subsequent probiotic encapsulation based on their fermentability to produce short-chain fatty acids (SCFAs), which are energy sources for intestinal epithelial cells, and the bacterial composition change in the gut microflora after the co-incubation with the fish gut suspensions. Alginate is the most common encapsulant for probiotic encapsulation due to its ability to gel with di-valent ions to provide bacteria with good gastric protection and a lack of toxicity. Kappa-carrageenan can crosslink with mono-valent ions, and it produced the most abundant SCFAs and could not be selectively utilized by pathogenic bacteria. Both needle extrusion and spray drying were explored as encapsulation techniques. Extrusion is easy to set up and mild to bacteria. Extrusion parameters, including the needle size, the polysaccharide concentration, the flow rate, and the extrusion temperature, were optimized to yield microparticles with sufficient gastric protection. The survivability of the probiotics that underwent the simulated gastric fluid remained at the same 8 Log CFU/g magnitude as before the challenge, while no survival was found for naked bacteria. The robust protection of needle-extruded particles was accompanied by difficulty releasing bacteria in the intestine, with only around 5 Log CFU/g could be released in 2 hours. Considering fish’s short digestion time, needle extrusion may not be optimal for probiotic delivery in aquaculture. Spray drying was adopted to resolve the release problem. The host-derived strain can withstand the spray drying condition and readily release in the simulated intestinal fluid with uncompromised protection in the gastric environment. The ex vivo co-incubation study confirmed that introducing this encapsulated host-derived isolate could effectively suppress the growth of Aeromonas. Future work includes the in vivo challenge test in jade perch to assess whether manipulating the host gut microbiota through host-derived probiotic supplementation can increase disease resistance and how the bacteria persist in their native environment.Singapore National Biofilm Consortiu

Liquorilactobacillus satsumensis from water kefir yields α-glucan polysaccharides with prebiotic and synbiotic qualities

Exopolysaccharides from water kefir grains are a potential source of novel, food-safe and functional materials. Herein, prebiotic properties of polysaccharides produced by water kefir-derived Liquorilactobacillus satsumensis bacteria were explored. Strains were cultured in sucrose-supplemented media for exopolysaccharides production, and partial hydrolysis was performed to yield shorter chain polysaccharides. Structural characterization revealed that hydrolyzed polysaccharides were branched glucans comprising α-1,6 bonds and α-1,3/α-1,4 branching, with molecular weight of ~10 kDa. Hydrolyzed polysaccharides demonstrated selective utilization by probiotics, but not by pathogens, and were non-digestible by human digestive enzymes. Particularly, hydrolyzed polysaccharides were fermentable by kefir-derived probiotics, and these were combined in a novel kefir synbiotic formulation. Using large bowel simulated conditions, it was demonstrated that hydrolyzed polysaccharides and kefir synbiotics promoted Bacteroidetes abundance, and increased acetate, propionate, and butyrate concentrations. Overall, hydrolyzed glucans from Liquorilactobacillus satsumensis have prebiotic properties with enhanced benefits in a synbiotic when combined with kefir probiotics.Ministry of Education (MOE)Nanyang Technological UniversitySingapore Food AgencySubmitted/Accepted versionThe authors would also like to acknowledge the financial support from the Singapore Centre for Environmental Life Sciences Engineering (SCELSE) (MOE/RCE: M4330019.C70), Ministry of Education AcRF-Tier 1 grant (RG19/18 and RT08/19), the Singapore National Biofilm Consortium (SNBC/2021/SF2/P04) and the Singapore Food Agency (SFS_RND_SUFP_001_06)